|Year : 2019 | Volume
| Issue : 2 | Page : 104-109
Basiliximab induction in living donor kidney transplant with tacrolimus-based triple immunosuppression
Shyam Bihari Bansal1, Deepak Pathania2, Sidharth Kumar Sethi1, Pranaw Kumar Jha1, Ashish Nandwani1, Manish Jain1, Amit Mahapatra1, Vijay Kher1
1 Department of Nephrology and Kidney Transplantation, Medanta Kidney and Urology Institute, Medanta-Medicity, Gurgaon, Haryana, India
2 Department of Nephrology, Shri Mata Vaishno Devi Narayana Superspeciality Hospital, Katra, Jammu and Kashmir, India
|Date of Submission||07-Dec-2018|
|Date of Acceptance||01-Mar-2019|
|Date of Web Publication||28-Jun-2019|
Dr. Shyam Bihari Bansal
Department of Nephrology and Kidney Transplantation, Medanta Kidney and Urology Institute, Medanta-Medicity, Sector 38, Gurgaon - 122 001, Haryana
Source of Support: None, Conflict of Interest: None
Introduction: Interleukin-2 receptor antagonists are recommended to reduce the risk of acute rejection (AR) in kidney transplant. This prospective study was undertaken to compare the incidence of AR with basiliximab induction as compared to no induction in first kidney recipients of living donors with tacrolimus (TAC)- and mycophenolate mofetil-based triple immunosuppression at 6 months. Methods: Two hundred and sixty patients were included in the study, 202 in the basiliximab group and 58 in the no induction group. Patients in the basiliximab group received two doses of 20 mg each on day 0 and day 4. The primary outcome was biopsy-proven AR at 6 months, and the secondary outcomes were incidence of infections and other adverse events along with graft and patient survival at the end of follow-up. All patients were followed up for a period of minimum 6 months. Results: There was no difference in baseline characteristics between the groups except higher human leukocyte antigen mismatch in the basiliximab group (3.80 ± 1.50 vs. 2.81 ± 1.53, P = 0.002). Forty-two (20.8%) patients in the basiliximab group developed AR at 6 months as compared to 10 (17.2%) in the no induction group (P = 0.55). There was no difference in adverse events between the groups. At a median follow-up of 1 year, graft survival (97% vs. 98.3%, P = 0.60) and patient survival (99% vs. 98.2%, P = 0.87) were also similar between the basiliximab and no induction groups, respectively. Conclusions: This study suggests that there is no advantage of using basiliximab induction in reducing AR in first kidney recipients of living donors in TAC-based triple immunosuppression.
Keywords: Basiliximab, induction, kidney transplant, living donor, tacrolimus
|How to cite this article:|
Bansal SB, Pathania D, Sethi SK, Jha PK, Nandwani A, Jain M, Mahapatra A, Kher V. Basiliximab induction in living donor kidney transplant with tacrolimus-based triple immunosuppression. Indian J Transplant 2019;13:104-9
|How to cite this URL:|
Bansal SB, Pathania D, Sethi SK, Jha PK, Nandwani A, Jain M, Mahapatra A, Kher V. Basiliximab induction in living donor kidney transplant with tacrolimus-based triple immunosuppression. Indian J Transplant [serial online] 2019 [cited 2019 Jul 19];13:104-9. Available from: http://www.ijtonline.in/text.asp?2019/13/2/104/261854
| Introduction|| |
Acute rejection (AR) remains an important cause of chronic rejection and graft loss., ARs occur most frequently within a few weeks of kidney transplant, so therapy to prevent AR is most intense during this period. Induction immunosuppression which is given in perioperative period and shortly afterward is used to reduce the incidence of AR within a few weeks of transplant. The most common drugs for induction worldwide are rabbit antithymocyte globulin (ATG), a polyclonal antibody preparation, which is a potent drug and is used mostly in patients with high immunological risk and monoclonal antibodies (mAb) against interleukin-2 receptors (IL-2Rs), which are not very potent and are used mainly for low-to-intermediate immunological risk recipients.
IL-2 receptor is present on all activated T-cells but not resting T-cells. Therapy with IL-2R antagonists (IL-2RAs) results in highly specific inhibition of lymphocytic immune response of activated T-cells, therefore suppressing T-cell activity against the allograft. Two types of nondepleting chimeric IL-2RA were developed: basiliximab (Novartis Pharma, Basel, Switzerland), which is a chimeric human–mouse IL-2RA, and daclizumab (Roche, Basel, Switzerland), which is humanized mouse mAb. Basiliximab is the only IL-2RA used for induction in kidney transplant recipients presently as daclizumab has been withdrawn from market by its manufacturer.
There are many studies in the past which have used IL-2RA as induction in kidney transplant and shown its effectiveness in reducing ARs.,, Two meta-analyses, mainly including cyclosporine-based dual or triple immunosuppression regimens, have shown benefit of using IL-2RA for the prevention of AR in kidney transplant recipients., Based on these studies and meta-analysis, the 2009 Kidney Disease Improving Global Outcomes guidelines recommend the use of IL-2RA in immunological low-risk recipients. In the modern era of immunosuppression, with availability of better and more potent immunosuppressive drugs such as tacrolimus (TAC) and mycophenolate mofetil (MMF), the utility of using induction in preventing AR is being questioned, especially in patients with low-to-intermediate immunological risk. In India, as most patients pay for their immunosuppression themselves without any insurance, so the cost is an important issue in maintaining long-term immunosuppression. The literature for the use of IL-2RA induction with TAC- and MMF-based immunosuppression is scarce in India. Therefore, we decided to undertake this prospective observational study to see the effect of IL-2RA induction on rates of AR as compared to no induction in our kidney transplant program.
| Materials and Methods|| |
All prospective living donor adult kidney transplant recipients admitted from November 1, 2014, to November 30, 2015, for transplant surgery at a tertiary care multi super-specialty hospital, who fulfilled the inclusion criteria, were enrolled. We planned to include 150 patients in each group. Patients were excluded if they were receiving cyclosporine/azathioprine-based or steroid-free protocol, ABO incompatible transplant, second or subsequent transplant, and recent or historic crossmatch positive. Deceased donor kidney transplants and patients who received rabbit ATG induction were also excluded from the study. After exclusion, the rest of the patients were offered the choice of opting for induction therapy with IL-2RA basiliximab, as the cost of therapy is usually borne by the patient. Informed and written consent was obtained from the patient. The study protocol was approved by the Institutional Review Board and Ethics Committee.
Patients opting for basiliximab induction were given two doses of 20 mg each on day 0 and day 4 of surgery. The drug was diluted in 100 ml normal saline and was administered over 1 h. All patients were started on capsule TAC at 0.1 mg/kg/day in two divided doses and tablet MMF/MMF sodium (MMF Na) at dose of 1000/720 mg twice daily one day prior to surgery. All patients also received one dose of intravenous methylprednisolone (IVMP) 500 mg perioperatively. TAC trough levels were monitored regularly and maintained at 8–12 ng/ml during the first 3 months, 6–8 ng/ml over the next 3 months, and 4–6 ng/ml thereafter. MMF Na/MMF was tapered to 720/1000 mg/day after 3 months in most of the patients. Prednisolone was tapered to 5–7.5 mg/day by the end of 3 months. Patients requiring dialysis within the first posttransplant week were classified as having delayed graft function (DGF). Patients underwent graft kidney biopsy on suspicion of AR unless it was not possible due to some reason. All biopsy samples were processed in house for light microscopy and immunofluorescence. Electron microscopy was done if required for diagnosis. The rejections were classified using the Banff criteria 2013. Patients were treated with IVMP 500 mg for three to five doses daily in case of acute cellular rejection (ACR), and patients with steroid-resistant rejection were given injection thymoglobulin (rabbit ATG, Sanofi Pharma) at a dose of 1.5 mg/kg/for 3–5 days on alternate days depending on clinical response and leukocyte counts. Patients with antibody-mediated rejection (AMR) were treated with plasmapheresis 1.5 volume and low-dose IV immunoglobulin 100 mg/kg on alternate days for 3–7 doses. After discharge, patients were followed as per institute protocol, and at each visit, kidney function and complete blood counts were monitored. TAC levels were monitored as required.
Patients were enrolled over a period of 12 months (starting November 1, 2014) and were followed in transplant outpatient department for a minimum of 6 months posttransplant. The primary endpoint of the study was the number of biopsy-proven AR (BPAR) episodes at 6 months. The secondary endpoints were serum creatinine, the incidence of new-onset diabetes after transplant (NODAT), infections, and patient and graft survival in both the groups till the last follow-up. The safety endpoints studied were infusion reactions, hypersensitivity reactions, and other adverse drug effects.
The data were reported as mean ± standard deviation or median and range wherever appropriate. Continuous variables were analyzed using Student's t-test or the Wilcoxon rank-sum test. The two treatment groups were compared using the Chi-square test, Mann–Whitney test, or Student's t-test as applicable. Survival estimates were calculated using Kaplan–Meier analyses for patient and graft survival. Fisher's exact test was used to compare the incidence of adverse events. Results were considered significant when P < 0.05.
All analysis was done with SPSS version 13 (IBM, Chicago, IL, USA) software. This study was approved by Medanta Hospital Institutional Review Board and Ethics Committee.
| Results|| |
Distribution of study population [Figure 1]
During the course of study, three hundred and fifty-seven patients underwent live donor kidney transplant at our center, of which 97 patients were excluded and 260 patients were included in the study. Two hundred and two out of 260 (77.7%) patients opted for basiliximab induction and 58 (22.3%) did not choose induction. In the basiliximab group and no induction group, 11 patients (5.4%) and 1 patient (1.7%), respectively, did not complete 6-month follow-up and were excluded from final analysis.
|Figure 1: The consortium diagram of the number of patients screened and excluded as per exclusion criteria. ATG: Antithymocyte globulin, IL-2RA: interleukin 2 receptor antagonists|
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Baseline characteristics[Table 1]
The mean age was 40.5 ± 12.7 years and 36.9 ± 12.01 years in the IL-2RA group and no induction group, respectively, which was not significantly different (P = 0.55). Similarly, there was no difference in gender and basic disease between the groups.
Eleven patients (5.4%) were HCV positive in the IL-2RA group while three patients (5.2%) were HCV positive in the no induction group (P = 0.61). Two patients were hepatitis B surface antigen (HBsAg) positive in the IL-2RA group as compared to four in the no induction group, which was statistically significant (P = 0.024).
Preemptive transplant and dialysis vintage were also similar between the groups; however, the mean human leukocyte antigen (HLA) mismatch was significantly higher in the IL-2RA group as compared to the no induction group (3.80 vs. 2.81; P = 0.002).
Acute rejections [Table 2]
Fifty-two patients (20%) had AR during the study period. In the basiliximab group, 42/202 (20.8%) patients developed AR within 6 months, while 10/58 (17.2%) patients developed AR in the no induction group, (P = 0.551). In IL2 RA group 38/42 acute rejections were ACR and rest 4 were AMR. In the no induction group, all 10/10 (100%) rejections were cellular, which again was not statistically different (P = 0.444). Six (14.7%) patients developed steroid-resistant rejection in the basiliximab group as compared to none in the no induction group. [Table 2] and [Figure 2] show the Banff grading of rejection in the two groups. During the study period, 87 (34.2%) patients underwent indication biopsies, 71/202 (35.1%) patients in the basiliximab group as compared to 16/58 (27.5%) in the no induction group, which was not different (P = 0.370). Most of the biopsies were performed in the first postoperative month in both the groups (67.6% and 75%) in the IL-2RA and no induction groups, respectively.
|Figure 2: Banff grading of rejection. AR: Acute rejection, ACR: Acute cellular rejection, BCR: Borderline cellular rejection, AMR: Antibody-mediated rejection|
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Secondary outcomes [Table 3]
Two patients in the IL-2RA group had DGF and one patient in both the groups required re-exploration. The mean serum creatinine in both the groups was similar till the last follow-up. The overall incidence of infection was similar in both the groups. The most common infections were urinary tract infections in both the groups. One patient in the IL-2RA group developed posttransplant lymphoproliferative disorder. The incidence of viral infections including CMV was also similar between the groups.
The incidence of new-onset diabetes (NODAT) was numerically higher in the IL-2 group; however, it did not reach statistically significant.
Patient and graft survival [Table 4]
There were seven graft losses during the study period. Six patients lost their graft in the IL-2RA group (graft survival: 97%) while one patient lost graft in the no induction group (graft survival: 98.3%), which was statistically insignificant (P = 0.60) [Figure 3]. In the IL-2RA group, four patients lost their grafts due to chronic AMR while one graft was lost to acute AMR and plasma cell-rich rejection each. One patient in the no induction group lost graft to plasma cell-rich rejection. There were two deaths in the IL-2RA group: one patient succumbed to multiple opportunistic infections while one patient had an acute coronary event. One patient in the no induction group died due to septic shock related to severe pneumonia. Patient survival was 99% and 98.2% in the two groups at the end of follow-up, which was statistically not different (P = 0.87) [Figure 4].
|Figure 3: Kaplan–Meier survival curves to compare graft survival in two groups|
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|Figure 4: Kaplan–Meier survival curves to compare patient survival in two groups|
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| Discussion|| |
KDIGO 2009 guidelines recommend IL-2RA as an induction agent in patients with low immunological risk (Grade 1B); however, the recommendation to use IL-2RA is based on studies and meta-analysis in which predominantly cyclosporine-based double or triple immunosuppression was used, and many studies used azathioprine as maintenance therapy.,, It is well known that TAC is a more potent immunosuppressive agent, and the use of TAC as compared to cyclosporine is associated with reduced rates of AR and better graft survival. The recent data with TAC- and MMF-based triple immunosuppression are rather equivocal in terms of AR episodes and graft survival in patients with or without IL-2 induction.,,
This is a prospective study in a large tertiary care private hospital in recipients of first kidney transplant from living donors, which is representative of transplant scenario in India. There was no difference in most baseline characteristics between the groups except number of HLA mismatches which were lower in the no induction group (2.81 ± 1.53) as compared to the IL-2RA group (3.8 ± 1.50, P = 0.002). As this study was not a randomized trial, so patients chose their induction after counseling with their nephrologist which might have led to selection bias.
The primary outcome of BPAR in the IL-2 group was 20.8% at the end of 6 months as compared to 17.2% in the no induction group, which was not significantly different (P = 0.551). The rate of AR is slightly higher which might be due to very low threshold of doing kidney biopsies as many rejections were borderline. The mean posttransplant day at the time of biopsy was 38 and 8 days, respectively, in the IL-2RA and no induction groups. This is an interesting finding as previous studies have demonstrated that two doses of basiliximab have half-life of 36 days and provide adequate drug level in the first posttransplant month., We could not do statistical testing as numbers were small. Hence, most ARs were delayed in the IL-2RA group as compared to the no induction group.
In 2010 Cochrane review on the use of IL-2RA in kidney transplant recipients, graft loss including death with a functioning graft was reduced by 25% at 6 months (16 studies: relative risk [RR] – 0.75, 95% confidence interval [CI] – 0.58–0.98). At 1 year, BPAR was reduced by 28% (14 studies: RR – 0.72, 95% CI – 0.64–0.81). The authors concluded that as compared to no induction, nine recipients would need treatment with IL-2RA to prevent one rejection and 42 to prevent one graft loss, per 100 recipients. However, only three studies had TAC-based immunosuppression in this review, and their subgroup analysis did not show any difference in AR (RR: 0.66; 95% CI: 0.28–1.57).
In a retrospective analysis of 28686 patients from scientific renal transplant registry of adult recipients from 2000 to 2008 with initial immunosuppression of TAC, MMF, and prednisolone with or without IL-2RA, the AR rate at 1 year was l1.6% and 13%, respectively, in the IL-2RA group as compared to the no induction group (P = 0.001); however, graft survival and patient survival were not different. The study concluded that benefit of IL-2RA induction with TAC- and MMF-based regimens is much less, and 70 patients need to be treated with IL-2RA to prevent 1 episode of AR as compared to 9 patients in cyclosporine-treated patients.
Lim et al. collected data from the Australia and New Zealand Dialysis and Transplant Registry on renal transplant recipients between 1995 and 2005 and showed no reduction in rejection risk with IL-2RA either in low-risk recipients treated with cyclosporine or intermediate immunological risk recipients treated with TAC-based regimen (RR: 0.90, 95% CI: 0.68–1.20; P = 0.48).
This study also mainly had low-risk recipients as all were first transplants with living donors and relatively high-risk patients such as second transplant and historic crossmatch positive, and patients who received thymoglobulin induction were excluded.
In a recent analysis of the United Nations of Organ Sharing registry data of living donor transplants between 2000 and 2012, Tanriover et al. found no difference in rates of ARs and graft failure at 1 year between the no induction and IL-2RA induction groups in patients on TAC, MMF, and steroid group in multivariate logistic and Cox regression analysis after propensity score matching (AR at 1 year: 11.7% vs. 12.4% [P = 0.55], similar graft survival at 5 years [P = 0.92]).
Gundlapalli et al. published an observational study from India, where Il2-RA efficacy was assessed in intermediate immunologic risk live donor renal transplants. A total of 46 patients on basiliximab induction were compared to risk-matched 56 controls at the end of 6 and 12 months posttransplant. The incidence of BPAR in the control group (12.5%, 6 months and 20.5%, 1 year) and the basiliximab group (13%, 6 months and 18.9%, 1 year) was similar. IL-2RA induction did not confer an additional advantage in the intermediate risk live donor transplants in patients on TAC- and MMF-based triple drug immunosuppression. There were some limitations in the study as the HLA matching was significantly different between the groups and details of blood transfusion were not available, both of which might affect rates of acute rejections. The Banff grading of ACR was not done. A number of patients were less, and out of them, one-fourth lost to follow-up within a year. In this study, 11/202 patients in the IL-2A group and only 1/58 patients in the no induction group were lost to follow-up after a median follow-up of 1 year.
There was no difference in serum creatinine at discharge and at the end of follow-up in this study.
To summarize, this prospective study in first living donor kidney transplant recipient shows no difference in the incidence of BPAR at 6 months in the IL-2RA group as compared to the no induction group and also shows a similar patient and graft survival at a median follow-up of 1 year.
There are some limitations to this study; first, this was not a randomized trial, which might have led to some selection bias, as more patients in the no induction group had better-matched kidneys. Second, there were fewer patients in the no induction group as compared to the IL-2 group (58 vs. 202). Third, limitation was not using panel reactive antibodies to define immunological risks; however, our patients were first transplant recipients of living donors with mean dialysis vintage of <6 months. The strength of the study was that it was a prospective study, and there was an excellent follow-up of patients and this pattern of immunosuppression reflects the actual scenario of patients in large private hospitals in India.
| Conclusions|| |
This study shows that the use of IL-2RA basiliximab induction does not reduce the incidence of AR at 6 months in recipients of first transplants with living donors in relatively low immunological risk recipients. There was no difference in adverse events and serum creatinine at 1 year. The patient survival and graft survival were also similar in induction with basiliximab versus no induction at a median follow-up of 1 year.
We would like to thank Dr. Rajesh Ahlawat and Dr. Prasoon Ghosh – transplant surgeons.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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